RU2476423C2 - Method of producing radioactive, fluorine-labelled organic compound - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing a radioactive, fluorine-labelled organic compound of formula

, involving a step of heating a compound of formula

at temperature of 40-90°C (where R¹ denotes a linear or branched alkyl with 1-10 carbon atoms or an aromatic substitute; R² denotes a linear or a branched halogen-alkylsuphonic acid substitute with 1-10 carbon atoms, a linear or branched alkylsulphonic acid substitute with 1-10 carbon atoms, a fluorosulphonic acid substitute or an aromatic sulphonic acid substitute, and R³ denotes a protective group) while stirring in an inert organic solvent in the presence of a phase transfer catalyst, ¹⁸F ions and calcium ions for radioactive fluorine labelling, and concentration of the phase transfer catalyst in the inert organic solvent is not less than 70 mmol/l.

EFFECT: disclosed method improves output of radioactive fluorination.

5 cl, 43 ex, 5 tbl, 6 dwg

Description

DESCRIPTION

TECHNICAL SUBSTANTIATION

The present invention relates to a method for producing a radioactive fluorine-labeled compound suitable for use in positron emission tomography and single photon emission computed tomography.

BACKGROUND

A radionuclide medical study, represented by positron emission tomography (hereinafter referred to as PET hereinafter) and single-photon emission computed tomography (hereinafter referred to as SPECT), is effective in diagnosing a number of diseases, including heart disease and cancer. Such methods include the administration of an agent labeled with a specific radioisotope (hereinafter referred to as the radiopharmaceutical), followed by the detection of gamma rays directly or indirectly emitted by the agent. A radionuclide medical study is characterized in that it not only has such excellent characteristics as high specificity and sensitivity to diseases, but also an advantage in providing information about the functionality of the lesions, compared with other research methods.

For example, [ ¹⁸ F] -2-fluoro-2-deoxy-D-glucose (hereinafter referred to as " ¹⁸ F-FDG"), one of the radiopharmaceuticals used for PET research, tends to concentrate in the area with increased glucose metabolism, thereby allowing specific detection of tumors in which glucose metabolism is elevated.

A radionuclide medical study is carried out by recording the distribution of the administered radiopharmaceutical, and the data obtained vary depending on the nature of the radiopharmaceutical. Therefore, for various diseases, various radiopharmaceuticals have been developed, and some of these drugs have found clinical application. For example, various agents for diagnosing tumors, agents for diagnosing blood flow, and agents for mapping receptors have been developed.

In recent years, a number of radioactive, halogen-labeled amino acid compounds have been developed as new radiopharmaceuticals, including [ ¹⁸ F] -1-amino-3-fluorocyclobutanecarboxylic acid (hereinafter referred to as [ ¹⁸ F] FACBC), and the clinical use of such drugs is considered (Patent Document 1 and Non-Patent Documents 1 and 2). [ ¹⁸ F] FACBC is considered an effective diagnostic agent for highly proliferative tumors because it has the property of being specifically absorbed by the amino acid transporter.

Regarding methods for producing [ ¹⁸ F] FACBC, methods are described which include: preparing 1- (N- (tert-butoxycarbonyl) amino) -3 - [((trifluoromethyl) sulfonyl) oxy] cyclobutane-1-carboxylic acid ester, in as a precursor for labeling, by replacing the triflate group in position 3 of the precursor with radioactive fluorine and deprotecting the resulting compound under acidic conditions (patent document 1 and non-patent documents 1 and 2).

Patent Document 1: Japanese Patent Laid-Open No. 2000-500442.

Non-Patent Document 1: Jonathan McConathy et al., "Improved synthesis of anti- [ ¹⁸ F] FACBC: improved preparation of labeling precursor and automated radiosynthesis.", Applied Radiation and Isotopes, (Netherlands), 2003, 58, p.657- 666.

Non-Patent Document 2: Timothy M. Shoup et al., "Synthesis and Evaluation of [ ¹⁸ F] 1-Amino-3-fluorocyclobutane-l-carboxylic Acid to Image Brain Tumors.", The Journal of Nuclear Medicine, 1999, 40, p. 313-338.

DESCRIPTION OF THE INVENTION

PROBLEMS SOLVED BY THE INVENTION

However, the product yield in the hitherto described method for producing [ ¹⁸ F] -FACBC (J. McConathy et al., Applied Radiation and Isotopes, 2003, 58, p. 657-666) is 12-24%. It is desirable for industrial production of [ ¹⁸ F] -FACBC to use conditions that stably provide a higher yield.

The preparation of [ ¹⁸ F] -FACBC includes, as a main step, a radioactive fluorination step consisting in attaching radioactive fluorine to a labeling precursor and a deprotection step consisting in deprotecting an intermediate obtained in the radioactive fluorination step. According to the conventional method, the stage of radioactive fluorination gives a yield of 12-42% (Japanese Patent Laid-open No. 2000-500442 and Timothy M. et al., J. Nuc. Med., 1999, 40, p. 313-338), and low yield at this stage is one of the reasons that reduce the yield of [ ¹⁸ F] -FACBC synthesis. Thus, in order to improve the synthesis yield of [ ¹⁸ F] -FACBC, it is necessary, first of all, to improve the stage of radioactive fluorination.

The present invention is made taking into account the above circumstances and is aimed at developing a production method that would stably provide a radioactive fluorine-labeled amino acid in the form of an [ ¹⁸ F] -1- (N- (tert-butoxycarbonyl) amino) -3-fluorocyclobutane- 1-carboxylic acid (hereinafter referred to as [ ¹⁸ F] Boc-FACBC), as an intermediate for [ ¹⁸ F] FACBC.

WAYS TO SOLVE PROBLEMS

As a result of the study, the present applicants found that a radioactive fluorine-labeled amino acid such as [ ¹⁸ F] Boc-FACBC can be stably obtained in high yield by setting the reaction temperature to 40-90 ° C and the concentration of the phase transfer catalyst in the reaction solution is not below a certain amount when carrying out the radioactive fluorination reaction, and thus, the present invention has been completed.

Thus, according to the present invention, a method for producing a radioactive fluorine-labeled organic compound is developed, which comprises the step of heating a compound represented by the following formula (1):

in an inert organic solvent in the presence of a phase transfer catalyst, ¹⁸ F ions and potassium ions, to obtain a compound represented by the following formula (2):

where the heating step is carried out at a heating temperature of 40-90 ° C, and the phase transfer catalyst is contained in an inert organic solvent at a concentration of at least 70 mmol / L.

In the production method of the present invention, the potassium ions used for the heating step are preferably contained in an inert organic solvent at a concentration of at least 27 mmol / L.

Also, in the production method of the present invention, the phase transfer catalyst is used in a molar ratio of not less than 0.7 relative to the compound represented by formula (1).

Further, in the production method of the present invention, the compound represented by formula (1) is contained in an inert organic solvent at a concentration of not less than 50 mmol / L.

According to a preferred embodiment of the present invention, a method for producing a radioactive fluorine-labeled organic compound of the invention comprises

a step for producing a mixture of a phase transfer catalyst, ¹⁸ F ions and potassium ions; and

the stage of radioactive fluorination, which consists in adding the compound represented by formula (1) and an inert organic solvent to the above mixture, and keeping the resulting reaction solution at a temperature of 40-90 ° C, with stirring, which gives the compound represented by formula (2).

In the above formulas (1) and (2), R ¹ means a linear or branched alkyl chain with 1-10 carbon atoms or an aromatic substituent, and preferably may mean a substituent selected from the group consisting of methyl group, ethyl group, tert- butyl group and phenyl group.

R ^{2 is} selected from the group consisting of a linear or branched haloalkyl sulfonic acid substituent with 1-10 carbon atoms, a linear or branched alkyl sulfonic acid substituent with 1-10 carbon atoms, a fluorosulfonic acid substituent and an aromatic sulfonic acid substituent, and preferably may mean a substituent selected from the group including methanesulfonic acid, toluenesulfonic acid, nitrobenzenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, fluorosulfonic acid y and perfluoroalkylsulfonic acid.

R ³ means a protective group and is not particularly limited, provided that it has the ability to prevent the interaction between radioactive fluorine and an amino group. More specifically, R ^{3 is} selected from the group consisting of various carbamate substituents, various amide substituents, various imide substituents and various amine substituents, and preferably a linear or branched alkyloxycarbonyl substituent with 2-7 carbon atoms, a linear or branched alkenyloxycarbonyl substituent with 3-7 carbon atoms, a benzyloxycarbonyl substituent with 7-12 carbon atoms that may have a substituent, an alkyldithiooxycarbonyl substituent with 2-7 carbon atoms, linear or branched an alkylamide substituent with 1-6 carbon atoms, a linear or branched alkenylamide substituent with 2-6 carbon atoms, a benzamide substituent with 6-11 carbon atoms, which may have a substituent, a cyclic imide substituent with 4-10 carbon atoms, an aromatic imine substituent with 6 to 11 carbon atoms, which may have a substituent, linear or branched alkylamino substituent with 1-6 carbon atoms, a linear or branched alkenylamine substituent with 2-6 carbon atoms and a benzylamine substituent with 6-11 carbon atoms which may have a substituent. More preferably, R ³ is a substituent selected from the group consisting of a tert-butoxycarbonyl group, an allyloxycarbonyl group, a phthalimide group and an N-benzylidene amine substituent, and most preferably a tert-butoxycarbonyl group or a phthalimide group.

In the method for producing a number of radioactive fluorine-labeled amino acids, such as the [ ¹⁸ F] -FACBC described so far, the radioactive fluorine labeling reaction is carried out using a phase transfer catalyst at a low concentration, i.e. in a molar ratio of about 0.3 relative to the precursor for labeling (Japanese Patent Laid-open No. 2000-500442, Timothy M. et al., J. Nuc. Med., 1999, 40, p. 313-338 and J. McConathy et al. , Applied Radiation and Isotopes, 2003, 58, p. 657-666). In contrast to such a standard disclosed method, the present applicants have determined that the concentration of the phase transfer catalyst in an inert organic solvent should be set to not lower than 70 mmol / L and, preferably, the phase transfer catalyst should be used in a molar ratio of at least 0.7 relative to the precursor for labeling, thereby, the fluorination yield is significantly improved, and a fluorine-labeled organic compound such as [ ¹⁸ F] -FACBC can be stably obtained in high yield. The amount of phase transfer catalyst is preferably equimolar or higher, expressed through the molar ratio relative to the precursor for labeling.

In addition, the present applicants have found that the yield from radioactive fluorination in the radioactive fluorination step can be improved by increasing the concentration of the precursor for labeling in the reaction solution. Based on the discovery made by the applicants, it was found that a fluorine-labeled amino acid such as [ ¹⁸ F] -FACBC can be obtained in higher yield by using a precursor concentration for labeling in an inert organic solvent of not less than a certain concentration.

Thus, the method according to another preferred embodiment of the present invention includes maintaining the concentration of the precursor for labeling in an inert organic solvent not lower than a certain concentration for the above method for producing a radioactive fluorine-labeled organic compound. More specifically, the concentration of the precursor in an inert organic solvent is preferably not less than 50 mmol / L, more preferably not less than 60 mmol / L, and particularly preferably not less than 70 mmol / L.

Moreover, the higher the concentration of the precursor for labeling in an inert organic solvent, the higher the yield at the stage of radioactive fluorination; however, since an increase in the concentration of the precursor with a constant amount of the precursor leads to a decrease in the total volume of the solution, the concentration must be such as to provide a sufficient amount of liquid to carry out the radioactive fluorination reaction. The upper limit of this concentration is determined by the used amount of the precursor for labeling, the volume of the reaction vessel, etc. For example, if the preparation is carried out using automatic synthesis equipment, the upper limit of the concentration of the reaction solution is 250 mmol / l, if the lower limit of the liquid volume that can be treated in the reaction vessel is 0.4 ml and the amount of the precursor for labeling used for the interaction equal to 0.1 mol. Similarly, the upper limit of the concentration of the reaction solution is 160 mmol / L if the lower limit of the liquid volume that can be treated in the reaction vessel is 0.5 ml and the amount of the precursor for labeling used for the reaction is 0.08 mmol.

As indicated above, the reaction temperature during the labeling reaction is 40-90 ° C. The reaction temperature reduces the reaction yield when it is too high or too low. A more preferred reaction temperature range is 50-80 ° C, and even more preferably 60-70 ° C.

According to the present invention, various solvents not reactive with [ ¹⁸ F] fluoride ion, phase transfer catalyst, potassium ion and precursor compound for labeling are useful as an inert organic solvent. Specific examples of an inert organic solvent include organic solvents containing at least one solvent selected from the group consisting of tetrahydrofuran, 1,4-dioxane, acetone, 2-butanone, dimethylformamide, dimethyl sulfoxide and acetonitrile, and preferably acetonitrile.

EFFECTS OF THE INVENTION

According to the preparation method of the present invention, during radioactive fluorination, the reaction temperature is set at 40-90 ° C and the concentration of the phase transfer catalyst is maintained at least 70 mmol / L, preferably with a concentration of potassium ion and / or precursor for labeling in an inert organic solvent, maintained at a certain concentration or higher, and a molar ratio of the phase transfer catalyst relative to the precursor for labeling, maintained at a certain amount or higher, so m, the yield in the preparation of a radioactive labeled fluorine amino acid such as ^[18 F] Boc-FACBC, can be improved.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, a method for producing a radioactive fluorine-labeled organic compound of the present invention is described in detail using the synthesis of [ ¹⁸ F] Boc-FACBC using ethyl 1- (N- (tert-butoxycarbonyl) amino) -3 - [((trifluoromethyl) ) sulfonyl) oxy] cyclobutane-1-carboxylic acid as a precursor for labeling.

According to a preferred embodiment, the production method of the present invention includes (1) a step for producing a mixture comprising an interfacial transfer catalyst, ^l8 F ions and potassium ions, and (2) a step for producing a radioactive fluorine-labeled organic compound by reacting a labeling precursor with the above mixture in order to ensure labeling with radioactive fluorine (stage of radioactive fluorination).

In the above step (1), radioactive fluorine can be obtained in a known manner, for example, by the method in which H ₂ ¹⁸ O-enriched water is used as a target and subjected to bombardment by protons. In this case, radioactive fluorine is present in the H ₂ ¹⁸ O-rich water used as a target. The H ₂ ¹⁸ O enriched water containing radioactive fluorine is passed through an anion exchange column so that the radioactive fluorine is adsorbed and collected on the column, thereby being released from the H ₂ ¹⁸ O enriched water. Then the potassium carbonate solution is passed through a column for the elution of radioactive fluorine, and the eluate is replenished with an interphase transfer catalyst and evaporated to dryness, thereby obtaining a mixture containing an interphase transfer catalyst, an ¹⁸ F ion and a potassium ion.

The amount of potassium carbonate used here is preferably adjusted to a value of 27 mmol / L or higher in terms of the concentration of potassium ions in the inert organic solvent used for the reaction solution. As is clear from the following comparison examples and examples, when the concentration of potassium ion in an inert organic solvent is less than 27 mmol / L, the yield of [ ¹⁸ F] fluorination at the stage of radioactive fluorination increases with the concentration of potassium ion, and at 27 mmol / L or higher the output becomes almost constant. Therefore, the use of the condition under which the concentration of potassium ion in an inert organic compound is 27 mmol / L or higher allows a more stable stage of radioactive fluorination in high yield.

On the other hand, it should be noted that when the amount of potassium carbonate is excessive, the reaction product can decompose under the influence of carbonate ions. In a preferred embodiment, the amount of potassium carbonate in terms of potassium ions can be approximately equivalent to the amount of phase transfer catalyst and, most preferably, the concentration and amount of potassium carbonate solution is adjusted so that the amount of phase transfer catalyst is in a molar ratio of about 1.3 relative to potassium ions.

Various compounds capable of forming a clathrate with an ¹⁸ F ion can be used as a phase transfer catalyst. In particular, various compounds useful for preparing organic compounds labeled with radioactive fluorine can be used; 18-crown-6 and other various aminopolyethers can be used. In a most preferred embodiment, KRYPTOFIX 222 (trademark, manufactured by Merck & Co., Inc.) can be used.

According to the present invention, the amount of phase transfer catalyst is controlled to provide a concentration of at least 70 mmol / L in an inert organic solvent, which is added later. As is clear from the comparison examples and examples below, the radioactive fluorination step can be stably performed in high yield by setting the amount of phase transfer catalyst in an inert organic solvent to at least 70 mmol / L. The amount of phase transfer catalyst is preferably not less than 0.7 in terms of a molar ratio relative to the labeling precursor, which is used later in the radioactive fluorination step. In a further preferred embodiment, the amount of phase transfer catalyst is equimolar or higher relative to the labeling precursor. In this case, the larger the amount of phase transfer catalyst, the greater the yield, but an excess amount of phase transfer catalyst is not preferable, since it is often difficult to sufficiently remove the excess phase transfer catalyst added in excess. In a preferred embodiment, the total amount of phase transfer catalyst may be 0.2 mmol or less, for example, when the amount of the precursor for labeling used is 80 μmol, the molar ratio of the phase transfer catalyst and the precursor for labeling is 2.5 or less. Such an amount of phase transfer catalyst can easily be removed by purification using a solid phase extraction column or the like in a subsequent step.

After the mixture containing the phase transfer catalyst, [ ¹⁸ F] ions and potassium ions was obtained by the above method, the radioactive fluorine-labeled amino acid is synthesized by performing the above step (2). In step (2), the precursor for labeling, the 1- (N- (tert-butoxycarbonyl) amino) -3 - [((trifluoromethyl) sulfonyl) oxy] cyclobutane-1-carboxylic acid ester is first added to the mixture containing the phase transfer catalyst transport, [ ¹⁸ F] ions and potassium ions. In a most preferred embodiment, the labeling precursor is first dissolved in an inert organic solvent and then added to the mixture. In this case, it is preferable to control the amount of inert organic solvent used so that the concentration of the precursor for labeling in the reaction solution during radioactive fluorination becomes at least 50 mmol / L, since the yield during radioactive fluorination is substantially improved.

After completion of the addition of the precursor for labeling and an inert organic solvent, the above reaction solution is subjected to radioactive fluorination by heating with stirring to obtain a radioactive fluorine-labeled organic compound as the target compound of the present invention. The reaction temperature is 40-90 ° C, preferably 50-80 ° C, and particularly preferably 60-70 ° C. The reaction time depends on the reaction temperature, and when the reaction temperature is 40-90 ° C, the reaction time is usually 3 minutes or more, preferably 3-15 minutes, and more preferably 3-7 minutes. It is expected that the longer the interaction time, the further the reaction of labeling with radioactive fluorine proceeds, but it should be noted that the decomposition of radioactive fluorine occurs simultaneously.

After completion of the reaction, purification is carried out in order to remove unreacted starting materials and phase transfer catalysts. In a most preferred embodiment, the purification is performed by the following methods. First, a solution is obtained by adding diethyl ether to the reaction solution, which completes the reaction. The resulting solution was passed through a silica gel solid phase column (eg, Sep-Pak (registered trademark), Silica (trademark, manufactured by Japan Waters), thereby obtaining [ ¹⁸ F] Boc-FACBC in the form of a diethyl solution.

EXAMPLE

Hereinafter, the present invention is disclosed in more detail using examples and comparison examples, not limiting the invention.

Moreover, in the examples and comparison examples, the radiochemical purity is determined by performing TLC analysis under the following conditions and using the following equation (1).

TLC analysis conditions:

Mobile phase: diethyl ether / hexane = 3/2

TLC plate: Silica Gel 60 F ₂₅₄ (trademark, surface layer thickness: 0.25 mm, manufactured by Merck & Co., Inc.)

Travel Length: 10 cm

TLC scanner: Rita Star (manufactured by Raytest)

Кроме того, выход [¹⁸F]-фторирования определяют по следующему уравнению (2).

In addition, the yield of [ ¹⁸ F] fluorination is determined by the following equation (2).

A: radioactivity of a mixture containing an interphase transfer catalyst, [ ¹⁸ F] ions and potassium ions (MBq)

B: Radioactivity of Synthesized [18F] -Boc-FACBC (MBq)

Comparison Example 1

Synthesis of ethyl ester syn-1- (N- (tert-butoxycarbonyl) amino) -3 - [((trifluoromethyl) sulfonyl) oxy] cyclobutane-1-carboxylic acid

Hydrolysis of syn-hydantoin (FIG. 1, stage 1)

250 ml of a saturated solution of barium hydroxide is added to 6.15 g (corresponding to 25 mmol) of syn-5- (3-benzyloxycyclobutane) hydantoin and refluxed by heating in an oil bath to 114 ° C for 24 hours or longer. Then, TLC analysis was performed using, as mobile solvents, two types of systems: a mixture of chloroform / methanol = 5/1 (Rf value for syn-hydantoin = about 0.6) and a mixture of chloroform / methanol = 95/1 (value Rf for syn-hydantoin = about 0.3), and confirm the completion of the interaction (staining in UV and phosphomolybdic acid).

After confirmation of completion of the reaction, the reaction solution was cooled to room temperature and about 24 ml of 1 mol / ml sulfuric acid was added to neutralize the reaction solution. After neutralization, the reaction solution was further stirred at room temperature for 5 minutes, and the precipitate formed was removed by filtration. The filtrate was concentrated to obtain 5.67 g of syn-1-amino-3-benzyloxycyclobutane-1-carboxylic acid as white crystals.

Ethyl esterification (FIG. 1, stage 2)

5.67 g of syn-1-amino-3-benzyloxycyclobutane-1-carboxylic acid, completely dried to remove water, was dissolved in 200 ml of ethanol. To the resulting solution was added 9.5 ml (corresponding to 75 mmol) of triethylamine and cooled to −78 ° C. over 20 minutes, and then 4.6 ml (corresponding to 62.5 mmol) of thionyl chloride were added. The reaction solution was stirred at 0 ° C for 1 hour and at room temperature for 1 hour, followed by refluxing while heating in an oil bath to 95 ° C overnight. The completion of the interaction is confirmed by TLC analysis using a mobile solvent, a mixture of chloroform / methanol = 95/1 (Rf value for the target compound = about 0.6) (confirmed by UV and phosphomolybdenum acid staining). After confirming completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 7.64 g of syn-1-amino-3-benzyloxycyclobutane-1-carboxylic acid ethyl ester as white crystals.

Joining Boc (FIG. 1, stage 3)

7.64 g of syn-1-amino-3-benzyloxycyclobutane-1-carboxylic acid ethyl ester was dissolved in 250 ml of a mixed solvent ethanol / triethylamine = 9/1. After cooling the solution in an ice bath for 15 minutes, 8.6 ml (corresponding 37.5 mmol) of di-tert-butyl dicarbonate was added to the solution and stirred at room temperature overnight. The completion of the interaction is confirmed by TLC analysis using a mobile solvent, hexane / ethyl acetate = 1: 1 (Rf value for the target compound = about 0.6) (confirmed by UV and molybdenum acid staining). After confirmation of the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain white crystals as a residue. 150 ml of chilled ethyl acetate and 150 ml of chilled 0.5 mol / L hydrochloric acid are added to the residue, stirred at room temperature for 5 minutes and left to stand until delamination occurs. The organic layer was extracted and washed with 150 ml of water, twice, 150 ml of a saturated aqueous solution of sodium bicarbonate, 150 ml of water, twice, and 150 ml of a saturated solution of sodium chloride, twice, in that order, dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain yellow oily substance. Separately, the aqueous layer was extracted and washed with 150 ml of ethyl acetate, twice, 150 ml of water, twice, and 150 ml of a saturated sodium chloride solution, in that order, dried with anhydrous sodium sulfate and concentrated under reduced pressure, releasing a small amount of a yellow oily substance. By these operations, 8.82 g of a light yellow oily substance are obtained. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain 8.04 g (corresponding to 23 mmol) of syn-1- (N- (tert-butoxycarbonyl) amino) -3-benzyloxycyclobutane-1 ethyl ester -carboxylic acid in the form of white crystals.

Debenzylation (FIG. 2, stage 4)

To 8.04 g (corresponding 23 mmol) of syn-1- (N- (tert-butoxycarbonyl) amino) -3-benzyloxycyclobutane-1-carboxylic acid ethyl ester was added 150 ml of ethanol and then 960 mg of palladium on activated carbon (10% palladium) for hydrogen substitution with stirring at room temperature overnight. After the reaction, the palladium on activated carbon was removed by filtration using celite, and the filtrate was concentrated under reduced pressure to obtain 5.74 g of white crystals as a residue. The interaction is monitored by TLC analysis using a mobile solvent, a mixture of hexane / ethyl acetate = 1/1 (Rf value for the target interaction compound = about 0.2) (confirmed by UV and ninhydrin staining) to confirm completion of the interaction. Then, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1, hexane / ethyl acetate = 4/1) to obtain 5.36 g (corresponding to 20.7 mmol) of syn-1- (N- (tert-butoxycarbonyl) amino) -3-hydroxycyclobutane-1-carboxylic acid as white crystals.

Triflation (FIG. 3, stage 5)

2.07 g (8 mmol) of syn-1- (N- (tert-butoxycarbonyl) amino) -3-hydroxycyclobutane-1-carboxylic acid ethyl ester was dissolved in 26 ml of pyridine and stirred in an ice bath for 20 minutes. Then, 2.0 ml (corresponding to 12 mmol) of trifluoromethanesulfonic anhydride are added and stirred for 30 minutes. The interaction is monitored by TLC analysis using a mobile solvent, a mixture of hexane / diethyl ether = 1/1 (Rf value for the target interaction compound = about 0.6) (confirmed by staining with ninhydrin) to confirm completion of the interaction. After confirming completion of the reaction, 100 ml of water and 100 ml of diethyl ether are added to the reaction solution, and extraction and washing with 100 ml of 1 mol / L hydrochloric acid, twice, 100 ml of water, twice, and 100 ml of a saturated sodium chloride solution, twice, are performed. specified order. After drying with anhydrous sodium sulfate, the concentration is carried out under reduced pressure to obtain 2.78 g of light yellow crystals. The reaction mixture was purified by silica gel chromatography (hexane / diethyl ether = 3/1) to give white crystals, and the resulting white crystals were recrystallized using pentane / diethyl ether to give 1.84 g (corresponding to 4.7 mmol) of ethyl ether syn-1- (N- (tert-butoxycarbonyl) amino) -3 - [((trifluoromethyl) sulfonyl) oxy] cyclobutane-1-carboxylic acid.

Comparison Examples 1-5, Examples 1-8

The [ ¹⁸ F] fluoride-containing H ₂ ¹⁸ O ion is passed through an anion exchange column to adsorb and collect the [ ¹⁸ F] fluoride ion on the column. Then, 0.3 ml of a solution of potassium carbonate at a concentration indicated in Table 1 is passed through an [ ¹⁸ F] -fluoride ion elution column, after which 0.3 ml of water is passed through a column and combined with the eluate. To the resulting solution was added 1.5 ml of Kryptofix 222 acetonitrile solution (trademark manufactured by Merck & Co., Inc.) in the amount indicated in table 1, and the radioactivity of the resulting mixture was measured (A: measured radioactivity in table 2).

Then, the mixture was heated to 110 ° C to evaporate water and acetonitrile and subjected to azeotropic distillation with the addition of acetonitrile (0.5 ml × 2), followed by evaporation to dryness. To the mixture was added a solution of syn-1- (N- (tert-butoxycarbonyl) amino) -3 - [((trifluoromethyl) sulfonyl) oxy] cyclobutane-1-carboxylic acid ethyl ester (hereinafter referred to as Boc-TfACBC) in an amount indicated in table 1, in acetonitrile, in the amount indicated in table 1, and heated to 83 ° C for 3 minutes with stirring. Then, the solution was allowed to cool for 5 minutes at room temperature, 4 ml of diethyl ether was added to the solution, and the mixture was passed through Sep-Pak Silica (trademark of Japan Waters) to give a solution of [ ¹⁸ F] Boc-FACBC in acetonitrile / diethyl ether in the form of a fluorine-labeled [ ¹⁸ F] compound. Radioactivity is measured, and the resulting radioactivity B (refers to Table 2) is used to calculate the fluorination yield [ ¹⁸ F]. Also, a TLC analysis of the obtained [ ¹⁸ F] Boc-FACBC is performed to determine radiochemical purity using the above equation (1).

In this case, the experiment under each condition is performed once in comparison examples 1 and 3 and example 3, twice in comparison examples 2 and 4 and example 8, four times in example 4 and three times in the rest.

Table 1
Experimental conditions in each example and comparison example (amount of each starting material used) Potassium Carbonate Concentration (mmol / L) The amount of Kryptofix 222 used (μmol) The number of Boc-TfACBC (μmol) Kryptofix 222 / Boc-TfACBC Ratio The added amount of acetonitrile (ml) Comparison Example 1 22 13 40 0.33 one Comparison Example 2 40 24 80 0.33 one Comparison Example 3 66.7 53 80 0.66 one Comparison Example 4 one hundred 60 80 0.75 one Comparison Example 5 66.7 53 40 1.3 one Example 1 one hundred 79.5 60 1.3 one Example 2 133 80 80 1,0 one Example 3 133 93 80 1,2 one Example 4 133 106 80 1.3 one Example 5 133 106 80 1.3 1,5 Example 6 133 120 80 1,5 one Example 7 167 133 one hundred 1.3 one Example 8 133 160 80 2.0 one

table 2
The measured values of radioactivity in each example and comparison example (values adjusted for the initiation of synthesis) A (MBq) In (MBq) Comparison Example 1 59.80 24.38 Comparison Example 2 1: 159.84; 2: 149.13 1: 88.73, 2: 69.59 Comparison Example 3 320.11 203.06 Comparison Example 4 1: 421.71; 2: 347.29 1: 308.17, 2: 216.28 Comparison Example 5 1: 211.91, 2: 187.64,
3: 371.63 1: 122.40, 2: 119.11,
3: 245.90 Example 1 1: 278.90, 2: 175.47,
3: 356.11 1: 193.63, 2: 117.86,
3: 252.20 Example 2 1: 500.23, 2: 273.51,
3: 355.39 1: 293.15, 2: 184.08,
3: 239.33 Example 3 461.47 326.44 Example 4 1: 112.29, 2: 445.79,
3: 149.01, 4: 126.74 1: 86.33, 2: 332.52,
3: 113.81, 4: 97.44 Example 5 1: 242.47, 2: 153.66,
3: 135.65 1: 165.59, 2: 101.35,
3: 93.59 Example 6 1: 123.95, 2: 433.30,
3: 330.94 1: 86.20, 2: 297.44,
3: 245.92 Example 7 1: 128.58, 2: 123.51,
3: 301.16 1: 98.64, 2: 86.89,
3: 218.30 Example 8 1: 123.10, 2: 112.36 1: 93.45, 2: 84.60

The results are shown in table 3 and in FIG. 4-6. The ratio of Kryptofix 222 used as the phase transfer catalyst and the Boc-TfACBC precursor (hereinafter referred to as the phase transfer catalyst / precursor ratio) is calculated and the relationship with the yield upon [ ¹⁸ F] fluorination is studied. The results are shown in FIG. 4. As follows from the figure, under conditions in which the phase transfer / precursor catalyst ratio is less than 0.7, the [ ¹⁸ F] Boc-FACBC yield upon [ ¹⁸ F] fluoridation improves significantly with increasing phase transfer / precursor catalyst ratio . Under conditions under which the interfacial transfer catalyst / precursor ratio is not lower than 0.7, the data indicate an almost constant yield, although there is data indicating a low yield during [ ¹⁸ F] fluorination (in comparison example 5), and the yield at [ ¹⁸ F] fluorination under such conditions is approximately 30-50% higher than in the conventional method (comparative example 1).

The relationship between the concentration of potassium ions in acetonitrile for the reaction solution and the yield at [ ¹⁸ F] fluorination is shown in FIG. 5. As follows from FIG. 5, under conditions under which the concentration of potassium ions is less than 27 mmol / L, the yield during [ ¹⁸ F] fluorination noticeably improves with increasing concentration of potassium ions, and at a concentration above that, the yield is almost constant. The relationship between the concentration of Kryptofix in acetonitrile for the reaction solution and the yield of [ ¹⁸ F] fluorination is shown in FIG. 6. As follows from FIG. 6, under conditions in which the concentration of Kryptofix in acetonitrile for the reaction solution (indicated as the concentration of the phase transfer catalyst in FIG. 6) is less than 70 mmol / L, the yield of [ ¹⁸ F] Boc-FACBC with [ ¹⁸ F] fluorination significantly increases with increasing concentration of Kryptofix, and at a concentration above that, the yield is almost constant. Thus, it was shown that [ ¹⁸ F] Boc-FACBC can be obtained in high yield by [ ¹⁸ F] fluorination under conditions in which the concentration of potassium ions is at least 27 mmol / L and the concentration of the phase transfer catalyst is at least 70 mmol / l. It is also shown that when these conditions are specified, in addition to the above condition, according to which the interfacial transfer catalyst / precursor ratio is not less than 0.7, a condition (comparison example 5) giving a low yield under conditions where the interfacial transfer catalyst / precursor ratio is not less than 0.7, can be eliminated, and thus, a more stable high yield can be achieved with [ ¹⁸ F] fluorination.

Based on the above results, it was found that [ ¹⁸ F] Boc-FACBC can be stably obtained in high yield by [ ¹⁸ F] fluorination, combining the condition under which the phase transfer catalyst / precursor ratio is at least 0.7, the condition wherein the concentration of potassium ions is at least 27 mmol / L; and the condition under which the concentration of the phase transfer catalyst is at least 70 mmol / L.

Table 3
The yield at [ ¹⁸ F] fluorination and the radiochemical purity of the compounds obtained in each example and comparison example The output at [ ¹⁸ F] -fluorination in% Radiochemical purity in% Comparison Example 1 24.16 59.27 Comparison Example 1 38.13 74.77 Comparison Example 3 54.75 86.32 Comparison Example 4 59.80 88.24 Comparison Example 5 56.66 90.65 Example 1 65.95 95.33 Example 2 61.39 95.36 Example 3 64.87 91.70 Example 4 73.53 96.52 Example 5 65.33 96.43 Example 6 67.98 95.92 Example 7 68.38 93.37 Example 8 70.73 93.57

Examples 9-43

The following experiments were performed at a reaction temperature of 40-100 ° C. to confirm that [ ¹⁸ F] Boc-FACBC could be obtained in good yield according to the preparation method of the present invention.

The [ ¹⁸ F] fluoride-containing H ₂ ¹⁸ O ion is passed through an anion exchange column to adsorb and collect the [ ¹⁸ F] fluoride ion on the column. Then, 0.3 ml of a solution of potassium carbonate at a concentration of 133 mmol / L is passed through a column for elution of [ ¹⁸ F] -fluoride ion, after which 0.3 ml of water is passed through a column and combined with the eluate. To the resulting solution was added 106 μmol of Kryptofix 222 (trademark manufactured by Merck & Co., Inc.) in 1.5 ml of acetonitrile.

The mixture was then heated to 110 ° C to evaporate water and subjected to azeotropic distillation with the addition of acetonitrile (0.5 ml × 2), followed by evaporation to dryness. To the resulting mixture was added a solution of 80 μmol of Boc-TfACBC in 1 ml of acetonitrile, and the reaction solution was stirred for the time period indicated in tables 4a-4d at the temperature indicated in tables 4a-4e, allowing the flow of radioactive fluorination. The resulting reaction solution was analyzed by TLC analysis, the% area of [ ¹⁸ F] Boc-FACBC was determined, and used as an indicator of yield for [ ¹⁸ F] fluorination.

In this case, the radioactivity used in each experiment is 414-759 MBq.

TLC analysis conditions:

TLC plate: Silica Gel 60 F ₂₅₄ (trademark; manufactured by Merck & Co., Inc.)

Mobile phase: diethyl ether / hexane = 1/1

Detector: Rita Star (trademark; manufactured by Raytest)

Table 4a
The reaction temperature and reaction time in each example Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 The reaction temperature, ° C 40 fifty 60 70 80 90 one hundred Time of interaction, min 3 3 3 3 3 3 3

Table 4b
The reaction temperature and reaction time in each example Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 Reaction
naya temperature, ° С 40 fifty 60 70 80 90 one hundred Interaction time, min 5 5 5 5 5 5 5

Table 4c
The reaction temperature and reaction time in each example Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Reaction temperature, ° C 40 fifty 60 70 80 90 one hundred Interaction time, min 7 7 7 7 7 7 7

Table 4d
The reaction temperature and reaction time in each example Example 30 Example 31 Example 32 Example 33 Example 34 Example 35 Example 36 The reaction temperature, ° C 40 fifty 60 70 80 90 one hundred Interaction time, min 10 10 10 10 10 10 10

Table 4e
The reaction temperature and reaction time in each example Example 37 Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 Reaction temperature
° C 40 fifty 60 70 80 90 one hundred Interaction time, min fifteen fifteen fifteen fifteen fifteen fifteen fifteen

The results are shown in tables 5a-5e. As follows from the above results, under conditions when the reaction time is 3-15 minutes, the yield at [ ¹⁸ F] fluorination is good, at least 62%, at all reaction temperatures. Also, an insignificant change is observed in the yield at [ ¹⁸ F] fluorination at reaction temperatures of at least 90 ° C, and thus it has been established that a good yield at [ ¹⁸ F] fluorination can be obtained at a reaction temperature of 40- 90 ° C.

Also, under conditions at which the reaction temperature is 50-80 ° C, the yield at [ ¹⁸ F] fluorination reaches at least 70% at all reaction times, and under conditions at which the reaction temperature is 60-70 ° C with [ ¹⁸ F] fluorination, it reaches at least 80% for all interaction times.

On the other hand, with regard to the reaction time, a particularly good yield with [ ¹⁸ F] fluorination is obtained when the reaction time is 3-7 minutes.

Thus, it was shown that with a reaction time of 3-15 minutes, a good yield with [ ¹⁸ F] fluorination can be achieved under conditions when the reaction temperature is 40-90 ° C or higher, a higher yield with [ ¹⁸ F] fluorination may be achieved at 50-80 ° C and, in particular, a good yield with [ ¹⁸ F] fluorination can be achieved at 60-70 ° C.

In addition, it was shown that an interaction time of at least 3 minutes is sufficient and an interaction time of 3-7 minutes is more preferable.

Table 5a
Exit at [ ¹⁸ F] fluoridation in each example Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Reaction temperature
° C 40 fifty 60 70 80 90 one hundred Time of interaction, min 3 3 3 3 3 3 3 Yield at [ ¹⁸ F] Fluoridation
at % 62 74 82 86 79 74 74

Table 5b
Exit at [ ¹⁸ F] fluoridation in each example Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 The reaction temperature, ° C 40 fifty 60 70 80 90 one hundred Time of interaction, min 5 5 5 5 5 5 5 Yield at [ ¹⁸ F] Fluoridation
at % 70 80 83 84 78 70 69

Table 5c
Exit at [ ¹⁸ F] fluoridation in each example Example 23 Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 The reaction temperature, ° C 40 fifty 60 70 80 90 one hundred Time of interaction, min 7 7 7 7 7 7 7 Yield at [ ¹⁸ F] Fluoridation
at % 74 81 81 83 76 72 73

Table 5d
Exit at [ ¹⁸ F] fluoridation in each example Example 30 Example 31 Example 32 Example 33 Example 34 Example 35 Example 36 The reaction temperature, ° C 40 fifty 60 70 80 90 one hundred Time of interaction, min 10 10 10 10 10 10 10 Yield at [ ¹⁸ F] Fluoridation
at % 76 83 83 81 76 67 70

Table 5e
Exit at [ ¹⁸ F] fluoridation in each example Example 37 Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 The reaction temperature, ° C 40 fifty 60 70 80 90 one hundred Time of interaction, min fifteen fifteen fifteen fifteen fifteen fifteen fifteen Yield at [ ¹⁸ F] Fluoridation
at % 78 83 81 82 74 69 68

INDUSTRIAL APPLICABILITY

The method for producing a radioactive fluorine-labeled organic compound of the present invention can be conveniently used to produce a radioactive fluorine-labeled organic compound, including [ ¹⁸ F] Boc-FACBC, used to produce new diagnostic agents.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a synthesis diagram of syn-1- (N- (t- butoxycarbonyl) amino) -3-benzyloxycyclobutane-1-carboxylic acid ethyl ester.

Figure 2 is a synthesis scheme for syn-1- (N- (t- butoxycarbonyl) amino) -3-hydroxycyclobutane-1-carboxylic acid ethyl ester.

Figure 3 is a synthesis scheme for the syn-1- (N- (tert-butoxycarbonyl) amino) -3 - [((trifluoromethyl) sulfonyl) oxy] cyclobutane-1-carboxylic acid ethyl ester.

Figure 4 is a graph expressing the relationship between the phase transfer catalyst / precursor for labeling and fluorination yield (triangle: examples, square: comparison examples).

Figure 5 is a graph expressing the relationship between the concentration of potassium ions and the yield during fluorination (triangle: examples, square: examples of comparison).

6 is a graph expressing the relationship between the concentration of the phase transfer catalyst and the yield upon fluorination (triangle: examples, square: comparison examples).

Claims (5)

1. A method of obtaining a radioactive fluorine-labeled organic compound, comprising the step of heating a compound represented by the following formula (I):

where R1 is a linear or branched alkyl chain with 1-10 carbon atoms or an aromatic substituent, R ² is a linear or branched haloalkyl sulfonic acid substituent with 1-10 carbon atoms, a linear or branched alkyl sulfonic acid substituent with 1-10 carbon atoms, a fluorosulfonic acid substituent or aromatic sulfonic acid Deputy, and R ³ means a protective group,
in an inert organic solvent in the presence of a phase transfer catalyst, ¹⁸ F ions and potassium ions, to obtain a compound represented by the following formula (2):

where R ¹ means a linear or branched alkyl chain with 1-10 carbon atoms or an aromatic substituent, R ³ means a protective group,
where the heating step is carried out at a heating temperature of 40-90 ° C and the phase transfer catalyst is contained in an inert organic solvent at a concentration of not less than 70 mmol / L. 2. The production method according to claim 1, in which potassium ions are contained in an inert organic solvent at a concentration of not less than 27 mmol / L. 3. The production method according to claim 1, in which the phase transfer catalyst is used in a molar ratio of not less than 0.7 relative to the compound represented by formula (1). 4. The production method according to claim 1, in which the compound represented by formula (1) is contained in an inert organic solvent at a concentration of not less than 50 mmol / L. 5. The production method according to any one of claims 1 to 4, including:
a step for producing a mixture of a phase transfer catalyst, ¹⁸ F ions and potassium ions, and
the stage of radioactive fluorination, which consists in adding the compound represented by the specified formula (1) and an inert organic solvent to the above mixture and keeping the resulting reaction solution at a temperature of 40-90 ° C, with stirring, which gives the compound represented by the specified formula (2).

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